While both infiltrating macrophages and glomerular cells are crucial in the pathogenesis of lupus nephritis (LN), one of the most common and dangerous clinical manifestations of SLE, their interactions remain incompletely understood. Appreciating the relative contribution of macrophages and resident kidney cells, and their interactions, would help us to understand the pathogenesis of LN and could provide an opportunity for more targeted therapies. Abnormal interaction of TNF-receptor superfamily members and their cognate ligands are believed to play a central role in lupus pathogenesis. Inhibition of several of these ligand/receptor pairs has already shown promise in clinical trials in human lupus. TWEAK is a secreted cytokine member of the TNF-ligand superfamily. TWEAK binds to its receptor, Fn14, and stimulates macrophages, fibroblasts, synoviocytes, and endothelial cells to secrete chemokines, cytokines, and other proinflammatory mediators. Our preliminary results suggest that TWEAK/Fn14 signaling is essential in the pathogenesis of LN: 1. Urinary TWEAK levels are increased in human LN, and correlate with disease activity;2. The TWEAK receptor, Fn14, is expressed by murine and human mesangial cells (MC) and podocytes in vitro, and in lupus kidneys in vivo. Treatment of podocytes with TWEAK leads to increased expression of key pathogenic cytokines, including MCP-1, RANTES, VCAM-1, and IP-10. Increased MCP-1 in the kidney leads to recruitment of inflammatory cells and amplification of the local inflammatory process;3. Injection of TWEAK to B6 mice increases MCP-1 expression, promotes chemotaxis of T cells and macrophages into the kidney, and stimulates glomerular cell proliferation;4. Preliminary studies show a beneficial effect of anti-TWEAK antibodies in reducing proteinuria in the chronic graft versus host murine model of SLE. Our hypotheses are that blocking TWEAK-Fn14 signaling will be beneficial in treatment of murine LN, and that TWEAK activation of both macrophages and resident kidney cells is central in the contribution of this cytokine to inflammatory renal disease in lupus.
Our Specific Aims for this proposal are as follows: I. Investigate the direct involvement of TWEAK-Fn14 signaling in the pathogenesis of LN and determine its therapeutic potential by a) characterizing lupus prone MRL-lpr/lpr (MRL-lpr) mice with Fn14 deficiency;and b) administering an anti- TWEAK monoclonal antibody (mAb) to lupus prone mice;II. Characterize the relative contribution of TWEAK activation in macrophages to the pathogenesis of LN;III. Determine the effect of TWEAK signaling in resident kidney cells, and particularly podocytes, in the development of LN, including albuminuria and glomerulosclerosis.

Public Health Relevance

A cytokine member of the TNF family of proteins, has many pro-inflammatory effects on several different cell types including mouse and human kidney cells. Some of the inflammatory mediators induced by TWEAK are important in the inflammation observed in kidneys affected by lupus. Our goals for this proposal are to investigate the importance of TWEAK binding to its receptor on different cell types in lupus, and to explore whether an anti-TWEAK antibody may be helpful in treating kidney inflammation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK090319-04
Application #
8715775
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Flessner, Michael Francis
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Sanz, Ana B; Izquierdo, M Concepcion; Sanchez-NiƱo, Maria Dolores et al. (2014) TWEAK and the progression of renal disease: clinical translation. Nephrol Dial Transplant 29 Suppl 1:i54-i62
Pawar, Rahul D; Goilav, Beatrice; Xia, Yumin et al. (2014) Serum autoantibodies in pristane induced lupus are regulated by neutrophil gelatinase associated lipocalin. Clin Immunol 154:49-65
Schwartz, Noa; Goilav, Beatrice; Putterman, Chaim (2014) The pathogenesis, diagnosis and treatment of lupus nephritis. Curr Opin Rheumatol 26:502-9
Gross, Rachael L; Schwartzman-Morris, Julie S; Krathen, Michael et al. (2014) A comparison of the malignancy incidence among patients with psoriatic arthritis and patients with rheumatoid arthritis in a large US cohort. Arthritis Rheumatol 66:1472-81
Labitigan, Monalyn; Bahce-Altuntas, Asena; Kremer, Joel M et al. (2014) Higher rates and clustering of abnormal lipids, obesity, and diabetes mellitus in psoriatic arthritis compared with rheumatoid arthritis. Arthritis Care Res (Hoboken) 66:600-7
Broder, Anna; Putterman, Chaim (2013) Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in systemic lupus erythematosus. J Rheumatol 40:30-3
Wen, Jing; Xia, Yumin; Stock, Ariel et al. (2013) Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway. J Autoimmun 43:44-54
Xia, Yumin; Janda, Alena; Eryilmaz, Ertan et al. (2013) The constant region affects antigen binding of antibodies to DNA by altering secondary structure. Mol Immunol 56:28-37